Premium
Bazedoxifene Induces Greater Vascular Responses than Estradiol Independent of Sex and GPER
Author(s) -
Zimmerman Margaret A.,
Lindsey Sarah H.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.999.5
Subject(s) - gper , endocrinology , medicine , selective estrogen receptor modulator , estrogen , estrogen receptor , mesenteric arteries , electrical impedance myography , sodium nitroprusside , phenylephrine , chemistry , vasodilation , nitric oxide , artery , breast cancer , blood pressure , cancer
Conjugated estrogens (CE) combined with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA) is a novel menopausal hormone therapy that provides a progestin‐free option for women with an intact uterus. While the impact of estrogen (E2) on the vascular system has been extensively studied, less is known about the response to BZA. Previous work from our laboratory shows that many of the beneficial actions of estrogen in the vasculature are mediated by the G protein‐coupled estrogen receptor (GPER). Since previous generation SERMs bind to GPER in various tissues, we hypothesized that BZA may induce greater vascular effects than estradiol due to increased GPER activation. Mesenteric resistance arteries were isolated from male and female wildtype (WT) and GPER knockout (KO) mice between 18–24 weeks old. Vessel reactivity was measured via wire myography in response to increasing doses of phenylephrine (PE), sodium nitroprusside (SNP), bazedoxifene acetate (BZA), and 17β‐estradiol (E2). In males, BZA‐induced relaxation was significantly greater than E2 in both WT (BZA: 84 ± 7% vs. E2: 50 ± 5%; P<0.001) and KO vessels (BZA: 72 ± 11% vs. E2: 55 ± 4%; P<0.001). Similarly, BZA was a better vasodilator than E2 in females (BZA: 94 ± 1% vs. E2: 57 ± 6%; P<0.001), and was not altered by GPER deletion (BZA: 93 ± 1% and E2: 60 ± 6%; ns). To further assess the impact of BZA on vessel reactivity, mesenteric arteries were pre‐treated with either 10 −9 M BZA, E2, or vehicle (0.1% DMSO) before being exposed to increasing doses of PE. In male WT and KO vessels, BZA blunted the response to PE‐induced contraction (WT Veh: 178 ± 11% vs. BZA: 145 ± 32%; P<0.001; KO Veh: 154 ± 5% vs. BZA: 120 ± 19%; P<0.001). This effect was exclusive to BZA and was not observed in male WT and KO vessels pre‐treated with E2 or DMSO (WT E2: 173 ± 20% and KO E2:160 ± 6%; ns). In female WT and KO arteries, pre‐treatment with BZA also opposed PE‐induced contraction (WT Veh: 159 ± 15% vs. BZA: 61 ± 10%; P<0.001; KO Veh: 173 ± 7% vs. BZA: 109 ± 20%; P<0.001), while E2 again failed to attenuate PE contraction (WT E2: 175 ± 20% and KO E2:189 ± 9%; ns). To assess whether BZA enhances nitric oxide‐induced relaxation, vessels were pre‐treated with BZA, E2, or DMSO prior to the SNP relaxation curve. Neither E2 nor BZA altered the response to SNP in male or female, WT or KO vessels. The current study demonstrates that BZA opposes vasoconstriction of mesenteric arteries to a greater degree than non‐selective E2, and this effect is independent of sex and GPER. Therefore, BZA may provide additional vascular benefits in menopausal hormone therapy and in turn promote a more positive cardiovascular profile in postmenopausal women. Support or Funding Information National Institutes of Health Grant 4R00HL103974 to S.H.L and American Heart Association Postdoctoral Fellowship Award #16POST27600001 to M.A.Z.